High Treatment Success Rates When Switching to Once Daily Nevirapine Containing Antiretroviral Therapy

INTRODUCTION: Two recent studies have highlighted low rates of virological response to once daily nevirapine containing combination antiretroviral therapy (CART) in treatment naïve HIV-1 infected subjects. AIM: We assessed factors associated with treatment responses in a cohort of HIV-1 infected, therapy naïve individuals, commencing nevirapine CART with two nucleoside reverse transcriptase inhibitors (NRTI) containing either lamivudine or emtricitabine. RESULTS: Between January 2002 and 2006, 173 subjects (80 female) met the study inclusion criteria. All subjects initially commenced on twice daily nevirapine with six different NRTI backbones. Mean follow up was 802 days. 49 (28%) subjects switched to once daily nevirapine, 23 (13%) within the first year. After 48 weeks of therapy, HIV RNA was < 50 copies/mL in 154/173 subjects (89%). A trend was observed towards improved virological outcome (HIV RNA < 50 copies/mL) and switching to once daily nevirapine during the first year of therapy (p=0.051). CONCLUSION: Whilst awaiting the results of prospective studies assessing once daily nevirapine, our data describe high treatment success rates and good safety responses when switching to once daily nevirapine

Steady-state pharmacokinetics of Nevirapine in HIV-1 infected adults in India

Background and Objectives: A variety of demographic factors, sex, and degree of immunosuppression can influence antiretroviral drug concentratians. The authors studied the influence of immune status, sex, and body mass index (BMI) on the steady-state pharmacokinetics of nevirapine delivered as a fixed-dose combination in HIV-1-infected patients in India. Methods: Twenty-six HIV-l-infected adult patients undergoing treatment with nevirapine-based highly active antiretroviral therapy regimens participated in the study. Pharmacokinetic variables were compared between patients divided based an CD4 cell counts, sex, and BMI. Results: Patients with higher BMI had lower peak and trough concentration and exposure of nevirapine than those with lower BMI; none of the differences in the pharmacokinetic variables of nevirapine between the various patient groups was statistically significant. Conclusions: Patients' immune status, sex, or BMI had no impact on the pharmacokinetics of nevirapine. Plasma nevirapine concentrations were maintained within the therapeutic range of the drug in the majority of the patients

Liver Enzyme Abnormalities and Associated Risk Factors in HIV Patients on Efavirenz-Based HAART with or without Tuberculosis Co-Infection in Tanzania.

To investigate the timing, incidence, clinical presentation, pharmacokinetics and pharmacogenetic predictors for antiretroviral and anti-tuberculosis drug induced liver injury (DILI) in HIV patients with or without TB co-infection. A total of 473 treatment naïve HIV patients (253 HIV only and 220 with HIV-TB co-infection) were enrolled prospectively. Plasma efavirenz concentration and CYP2B6*6, CYP3A5*3, *6 and *7, ABCB1 3435C/T and SLCO1B1 genotypes were determined. Demographic, clinical and laboratory data were collected at baseline and up to 48 weeks of antiretroviral therapy. DILI case definition was according to Council for International Organizations of Medical Sciences (CIOMS). Incidence of DILI and identification of predictors was evaluated using Cox Proportional Hazards Model. The overall incidence of DILI was 7.8% (8.3 per 1000 person-week), being non-significantly higher among patients receiving concomitant anti-TB and HAART (10.0%, 10.7 per 1000 person-week) than those receiving HAART alone (5.9%, 6.3 per 1000 person-week). Frequency of CYP2B6*6 allele (p = 0.03) and CYP2B6*6/*6 genotype (p = 0.06) was significantly higher in patients with DILI than those without. Multivariate cox regression model indicated that CYP2B6*6/*6 genotype and anti-HCV IgG antibody positive as significant predictors of DILI. Median time to DILI was 2 weeks after HAART initiation and no DILI onset was observed after 12 weeks. No severe DILI was seen and the gain in CD4 was similar in patients with or without DILI. Antiretroviral and anti-tuberculosis DILI does occur in our setting, presenting early following HAART initiation. DILI seen is mild, transient and may not require treatment interruption. There is good tolerance to HAART and anti-TB with similar immunological outcomes. Genetic make-up mainly CYP2B6 genotype influences the development of efavirenz based HAART liver injury in Tanzanians

Adverse Events in a Cohort of HIV Infected Pregnant and Non-Pregnant Women Treated with Nevirapine versus Non-Nevirapine Antiretroviral Medication

BACKGROUND: Predictors of adverse events (AE) associated with nevirapine use are needed to better understand reports of severe rash or liver enzyme elevation (LEE) in HIV+ women. METHODOLOGY: AE rates following ART initiation were retrospectively assessed in a multi-site cohort of 612 women. Predictors of onset of rash or LEE were determined using univariate and multivariate analyses. PRINCIPAL FINDINGS: Of 612 subjects, 152 (24.8%) initiated NVP-based regimens with 86 (56.6%) pregnant; 460 (75.2%) initiated non-NVP regimens with 67 (14.6%) pregnant. LEE: No significant difference was found between regimens in the development of new grade ≥2 LEE (p  =  0.885). Multivariate logistic regression demonstrated an increased likelihood of LEE with HCV co-infection (OR 2.502, 95% CI: 1.04 to 6, p =  0.040); pregnancy, NVP-based regimen, and baseline CD4 >250 cells/mm(3) were not associated with this toxicity. RASH: NVP initiation was associated with rash after controlling for CD4 and pregnancy (OR 2.78; 95%CI: 1.14-6.76), as was baseline CD4 >250 cells/mm(3) when controlling for pregnancy and type of regimen (OR 2.68; 95% CI: 1.19-6.02 p  =  0.017). CONCLUSIONS: CD4 at initiation of therapy was a predictor of rash but not LEE with NVP use in HIV+ women. Pregnancy was not an independent risk factor for the development of AEs assessed. The findings from this study have significant implications for women of child-bearing age initiating NVP-based ART particularly in resource limited settings. This study sheds more confidence on the lack of LEE risk and the need to monitor rash with the use of this medication

Dose adjustment of the non-nucleoside reverse transcriptase inhibitors during concurrent rifampicin-containing tuberculosis therapy: one size does not fit all

Importance of the field: HIV/tuberculosis (TB) co-infection is common and associated with high mortality. Simultaneous highly active antiretroviral therapy during TB treatment is associated with substantial survival benefit but drug–drug interactions complicate NNRTI dosing. Areas covered in this review: We reviewed the impact of rifampicin-containing TB therapy on the NNRTIs pharmacokinetics and clinical outcome. PubMed database was searched from 1966 to July 2009 using the terms efavirenz, rifampicin, nevirapine, pharmacokinetics, pharmacogenetics, HIV, TB, CYP2B6, CYP3A4 and metabolism. References from identified articles and abstracts from meetings were also reviewed. What the reader will gain: A comprehensive review of the literature on this subject including pharmacokinetic and clinical studies. Most studies were small, observational or underpowered to detect the true effect of rifampicin on NNRTI-based therapy. None of the studies were controlled for genetic factors and there were limited data on children. Take home message: There were insufficient data to make definitive recommendations about dose adjustment of the NNRTIs during rifampin-containing therapy. Current data suggest that the standard dose of efavirenz or nevirapine is adequate in most HIV/TB co-infected adults. However, more research is needed in pediatric populations as well as to define role of drug–gene interactions

The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV and tuberculosis.

Purpose: Drug interactions are of concern when treating patients co-infected with human immunodeficiency virus (HIV) and tuberculosis. Concomitant use of efavirenz (EFV) with the enzyme inducer rifampicin might be expected to increase EFV clearance. We investigated the influence of concomitant tuberculosis treatment on the plasma clearance of EFV. Methods: Fifty-eight patients were randomized to receive their EFV-containing antiretroviral therapy either during or after tuberculosis treatment. Steady-state EFV plasma concentrations (n = 209 samples) were measured, 83 in the presence of rifampicin. Data were analyzed using a non-linear mixed effects model, and the model was evaluated using non-parametric bootstrap and visual predictive checks. Results: The patients had a median age of 32 (range 19–55) years and 43.1% were women. There was a bimodal distribution of apparent clearance, with slow EFV metabolizers accounting for 23.6% of the population and having a metabolic capacity 36.4% of that of the faster metabolizers. Apparent EFV clearance after oral administration in fast metabolizers was 12.9 L/h/70 kg whilst off tuberculosis treatment and 9.1 L/h/70 kg when on tuberculosis treatment. In slow metabolizers, the clearance estimates were 3.3 and 4.7 L/h/70 kg in the presence and absence of TB treatment, respectively. Overall there was a 29.5% reduction in EFV clearance during tuberculosis treatment. Conclusion: Unexpectedly, concomitant rifampicin-containing tuberculosis treatment reduced apparent EFV clearance with a corresponding increase in EFV exposure. While the reasons for this interaction require further investigation, cytochrome P450 2B6 polymorphisms in the population studied may provide some explanation